PT1883397E - Dispersible bosertan tablet - Google Patents
Dispersible bosertan tablet Download PDFInfo
- Publication number
- PT1883397E PT1883397E PT06744942T PT06744942T PT1883397E PT 1883397 E PT1883397 E PT 1883397E PT 06744942 T PT06744942 T PT 06744942T PT 06744942 T PT06744942 T PT 06744942T PT 1883397 E PT1883397 E PT 1883397E
- Authority
- PT
- Portugal
- Prior art keywords
- dispersible tablet
- weight based
- total
- tablet
- total amount
- Prior art date
Links
- 239000007919 dispersible tablet Substances 0.000 claims abstract description 71
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 239000003826 tablet Substances 0.000 claims description 25
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- 239000000314 lubricant Substances 0.000 claims description 11
- 235000003599 food sweetener Nutrition 0.000 claims description 10
- 239000003765 sweetening agent Substances 0.000 claims description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 9
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 9
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000000796 flavoring agent Substances 0.000 claims description 8
- 235000013355 food flavoring agent Nutrition 0.000 claims description 8
- 108010011485 Aspartame Proteins 0.000 claims description 7
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims description 7
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 7
- 239000000605 aspartame Substances 0.000 claims description 7
- 235000010357 aspartame Nutrition 0.000 claims description 7
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical group OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 7
- 229960003438 aspartame Drugs 0.000 claims description 7
- 239000001506 calcium phosphate Substances 0.000 claims description 7
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 7
- 229940038472 dicalcium phosphate Drugs 0.000 claims description 7
- 229910000390 dicalcium phosphate Inorganic materials 0.000 claims description 7
- 235000002906 tartaric acid Nutrition 0.000 claims description 7
- 239000011975 tartaric acid Substances 0.000 claims description 7
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 6
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 6
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 150000004682 monohydrates Chemical class 0.000 claims description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012748 slip agent Substances 0.000 claims description 6
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 5
- 229960004998 acesulfame potassium Drugs 0.000 claims description 5
- 239000000619 acesulfame-K Substances 0.000 claims description 5
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 5
- 239000007884 disintegrant Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000000454 talc Substances 0.000 claims description 5
- 229910052623 talc Inorganic materials 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 claims description 4
- 238000007907 direct compression Methods 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 3
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000002535 acidifier Substances 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- 239000008119 colloidal silica Substances 0.000 claims description 3
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 239000008109 sodium starch glycolate Substances 0.000 claims description 3
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical group OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 240000009088 Fragaria x ananassa Species 0.000 claims description 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 240000008790 Musa x paradisiaca Species 0.000 claims description 2
- 235000018290 Musa x paradisiaca Nutrition 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 239000004376 Sucralose Substances 0.000 claims description 2
- 244000290333 Vanilla fragrans Species 0.000 claims description 2
- 235000009499 Vanilla fragrans Nutrition 0.000 claims description 2
- 235000012036 Vanilla tahitensis Nutrition 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
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- 150000004781 alginic acids Chemical class 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 229940099112 cornstarch Drugs 0.000 claims description 2
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 claims description 2
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
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- 239000010514 hydrogenated cottonseed oil Substances 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
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- 235000019793 magnesium trisilicate Nutrition 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 229920003124 powdered cellulose Polymers 0.000 claims description 2
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- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 229960001462 sodium cyclamate Drugs 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 235000012222 talc Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- 239000004067 bulking agent Substances 0.000 claims 1
- 150000003445 sucroses Chemical class 0.000 claims 1
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 abstract description 6
- 238000004090 dissolution Methods 0.000 description 9
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- 238000009472 formulation Methods 0.000 description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 4
- 229960003065 bosentan Drugs 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- BYNVYIUJKRRNNC-UHFFFAOYSA-N docosanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCCCCCCCC(O)=O BYNVYIUJKRRNNC-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- -1 hydrates Chemical class 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
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- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
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- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 244000307700 Fragaria vesca Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229960005164 acesulfame Drugs 0.000 description 1
- YGCFIWIQZPHFLU-UHFFFAOYSA-N acesulfame Chemical compound CC1=CC(=O)NS(=O)(=O)O1 YGCFIWIQZPHFLU-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N beta-monoglyceryl stearate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
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- 229930002875 chlorophyll Natural products 0.000 description 1
- 235000019804 chlorophyll Nutrition 0.000 description 1
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 1
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- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
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- 235000013980 iron oxide Nutrition 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
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- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Description
11
DESCRIÇÃO "COMPRIMIDO DISPERSIVEL DE BOSENTANO" A presente invenção refere-se aos comprimidos dispersiveis compreendendo o composto 4-terc-butil-N-[6-(2-hidroxi-etoxi)-5-(2-metoxi-fenoxi)-2-(pirimidin-2-il)-pirimidin-4-il]-benzeno-sulfonamida, o citado composto sendo daqui em diante referido como composto I. 0 composto I possui a seguinte fórmula:DESCRIPTION " BOSENTANE DISPERSIBLE TABLET " The present invention relates to dispersible tablets comprising 4-tert-butyl-N- [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- (pyrimidin-2-yl) -pyrimidin-4-yl] -benzenesulfonamide, said compound being hereinafter referred to as compound I. The compound I has the following formula:
0 composto I é um inibidor de receptor de endotelina e útil para o tratamento de hipertensão arterial pulmonar (PAH). 0 composto I e a sua preparação são descritos em EP 0526708 Al. O Bosentano (Tracleer®) é um tratamento oral para PAH (Classes III e IV nos Estados Unidos, Classe III na Europa) . O Bosentano é um antagonista de receptor de endotelina dual com afinidade por ambos os receptores de endotelina ETA e ETB, prevenindo deste modo os efeitos prejudiciais de ET-1. Como conhecido do World Standard Drug Database, a formulação comercial disponível possui a seguinte composição: Bosentano (125 ou 62,5mg), amido, 2 triacetina, estearato de magnésio, talco, óxido férrico, povidona, dióxido de titânio, etilcelulose, beenato de glicerilo, hipromelose e amido-glicolato de sódio.Compound I is an endothelin receptor inhibitor and useful for the treatment of pulmonary arterial hypertension (PAH). Compound I and its preparation are described in EP 0526708 A1. Bosentan (Tracleer®) is an oral treatment for PAH (Classes III and IV in the United States, Class III in Europe). Bosentan is a dual endothelin receptor antagonist with affinity for both ETA and ETB endothelin receptors, thereby preventing the deleterious effects of ET-1. As known from the World Standard Drug Database, the commercial formulation available has the following composition: Bosentan (125 or 62.5mg), starch, 2-triacetin, magnesium stearate, talc, ferric oxide, povidone, titanium dioxide, ethylcellulose, glyceryl, hypromellose and sodium starch glycolate.
No contexto desta descrição, qualquer referência ao composto I é para ser entendida como se referindo também aos sais ou solvatos farmaceuticamente aceitáveis, incluindo hidratos, de Composto I, bem como às suas formas morfológicas, se não indicado de outro modo e onde apropriado e expediente. "Comprimido dispersível" significa um comprimido, que se desintegra completamente em água a 15-22°C em não mais do que 5 minutos ou preferivelmente menos de 4 minutos. Noutra forma de realização, os comprimidos dispersiveis da presente invenção possuem um tempo de desintegração menor do que 3 minutos, preferivelmente menor do que 2 minutos ou mais preferivelmente menor do que 1 minuto (método de desintegração de acordo com a Farmacopeia europeia, EP). 0 presente fármaco de composto I é actualmente comercializado como um comprimido para o tratamento de PAH, uma doença mortal se não tratada. As crianças têm dificuldades para ingerir comprimidos, assim a formulação de comprimido actualmente comercializada não é conveniente para administração a crianças. Um fármaco na forma de uma suspensão será mais benéfico para crianças. A presente invenção portanto refere-se ao desenvolvimento de um comprimido, que pode ser dispersado em água para formar uma suspensão antes da administração. 0 comprimido dispersível deve desintegrar-se completamente em água a 15-22°C em menos do que 5 minutos ou preferivelmente menos do que 4 minutos. Noutra forma de realização, os comprimidos 3 dispersíveis da presente invenção possuem um tempo de desintegração menor do que 3 minutos, preferivelmente menor do que 2 minutos ou mais preferido menor do que 1 minuto baseado no método de acordo com a Farmacopeia europeia (método de desintegração de acordo com EP).In the context of this description, any reference to compound I is to be understood as referring also to the pharmaceutically acceptable salts or solvates, including hydrates, of Compound I, as well as to their morphological forms, if not otherwise indicated and where appropriate and expedient . " Dispersible tablet " means a tablet, which disintegrates completely in water at 15-22 ° C in not more than 5 minutes or preferably less than 4 minutes. In another embodiment, the dispersible tablets of the present invention have a disintegration time of less than 3 minutes, preferably less than 2 minutes or more preferably less than 1 minute (disintegration method according to European Pharmacopoeia, EP). The present compound I drug is currently marketed as a tablet for the treatment of PAH, a deadly disease if untreated. Children have difficulty in ingesting tablets, so the currently marketed tablet formulation is not suitable for administration to children. A drug in the form of a suspension will be more beneficial for children. The present invention therefore relates to the development of a tablet, which may be dispersed in water to form a suspension prior to administration. The dispersible tablet should disintegrate completely in water at 15-22 ° C in less than 5 minutes or preferably less than 4 minutes. In another embodiment, the dispersible tablets of the present invention have a disintegration time of less than 3 minutes, preferably less than 2 minutes or more preferred less than 1 minute based on the method according to the European Pharmacopoeia (disintegration method according to EP).
Outras vantagens da formulação pediátrica são as seguintes: • Melhor adesão à terapêutica devido à formulação pediátrica especial. • Agora é possível dar aos pacientes pediátricos uma dose optimizada e individualizada de acordo com o peso corporal. • A formulação pediátrica tem uma absorção demonstrada baseada em dados de pk. A presente invenção proporciona um tal comprimido dispersivel adequado para crianças compreendendo: (a) o composto I e (b) excipientes farmaceuticamente aceitáveis adequados para a preparação de comprimidos dispersíveis. A quantidade de composto I, calculada como a percentagem de conteúdo em peso de grupo activo, baseada no peso total de comprimido dispersivel, é 5% a 40%, preferivelmente entre 8% a 30%. Em particular, a quantidade de composto I como composto activo pode variar de 10% a 17%.Other advantages of pediatric formulation are the following: • Better adherence to therapy due to special pediatric formulation. • It is now possible to give pediatric patients an optimized and individualized dose according to body weight. • The pediatric formulation has demonstrated absorption based on pk data. The present invention provides such a dispersible tablet suitable for children comprising: (a) compound I and (b) pharmaceutically acceptable excipients suitable for the preparation of dispersible tablets. The amount of compound I, calculated as the percentage content by weight of active group, based on the total weight of the dispersible tablet, is 5% to 40%, preferably 8% to 30%. In particular, the amount of compound I as the active compound may range from 10% to 17%.
Numa modalidade preferida da invenção, a presente invenção proporciona um comprimido dispersivel no qual composto I está na forma de mono-hidrato.In a preferred embodiment of the invention, the present invention provides a dispersible tablet in which compound I is in the form of a monohydrate.
Um ou mais excipientes farmaceuticamente aceitáveis podem estar presentes no comprimido dispersivel, p.ex. 4 cargas (1.1), desintegrantes (1.2), agentes de deslizamento (1.3), agentes acidulantes (1.4), agentes aromatizantes (1.5), agentes edulcorantes (1.6), e lubrificantes (1.7). É feita referência à extensa literatura sobre o tema para estes e outros excipientes farmaceuticamente aceitáveis e procedimentos aqui mencionados, veja em particular Handbook of Pharmaceutical Excipients, Terceira edição, editado por Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA e Pharmaceutical Press, London; e Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete editado por Η. P. Fiedler, 4a Edição, Edito Cantor, Aulendorf e edições anteriores.One or more pharmaceutically acceptable excipients may be present in the dispersible tablet, eg 4 fillers (1.1), disintegrating agents (1.2), slip agents (1.3), acidulants (1.4), flavoring agents (1.5), sweetening agents 1.6), and lubricants (1.7). Reference is made to the extensive literature on the subject for these and other pharmaceutically acceptable excipients and procedures mentioned herein, see in particular Handbook of Pharmaceutical Excipients, Third Edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete edited by Η. P. Fiedler, 4th Edition, Edito Cantor, Aulendorf and previous editions.
Cargas (1.1) de acordo com a invenção incluem mas não são restritas a celulose microcristalina, fosfato de dicálcio, lactose e amido pré-gelatinizado. Preferivelmente, celulose microcristalina é usada em combinação com fosfato de dicálcio.Loads (1.1) according to the invention include but are not restricted to microcrystalline cellulose, dicalcium phosphate, lactose and pregelatinized starch. Preferably, microcrystalline cellulose is used in combination with dicalcium phosphate.
Desintegrantes (1.2) adequados de acordo com a invenção incluem mas não são restritos a croscarmelose de sódio, amido-glicolato de sódio, amido de milho, CMC-Ca, CMC-Na, celulose microcristalina, PVP reticulada, p.ex. conhecida e comercialmente disponível sob as designações comerciais Crospovidone, Polyplasdone, comercialmente disponível junto de ISP company ou Kollidon® XL, ácido algínico, alginato de sódio, amido pré-gelatinizado, e goma guar. Preferivelmente, croscarmelose de sódio, p.ex. Ac-Di-Sol® é usado.Suitable disintegrators (1.2) according to the invention include but are not limited to croscarmellose sodium, sodium starch glycolate, corn starch, CMC-Ca, CMC-Na, microcrystalline cellulose, cross-linked PVP, e.g. commercially available under the trade names Crospovidone, Polyplasdone, commercially available from ISP company or Kollidon XL, alginic acid, sodium alginate, pregelatinized starch, and guar gum. Preferably, croscarmellose sodium, e.g. Ac-Di-Sol® is used.
Como agentes de deslizamento (1.3), um ou mais dos seguintes podem ser usados: sílica; sílica coloidal, p.ex. sílica coloidal anidra, p.ex. Aerosil® 200, trissilicato de 5 magnésio, celulose em pó, amido e talco. Preferivelmente, é usado dióxido de silício coloidal. Agentes acidulantes (1.4) incluem mas não são restritos a ácido tartárico, ácido cítrico, ácido ascórbico, ácido láctico, e ácido fumárico. De preferência é usado ácido tartárico.As slip agents (1.3), one or more of the following may be used: silica; colloidal silica, eg anhydrous colloidal silica, eg Aerosil® 200, magnesium trisilicate, powdered cellulose, starch and talc. Preferably, colloidal silicon dioxide is used. Acidulating agents (1.4) include but are not restricted to tartaric acid, citric acid, ascorbic acid, lactic acid, and fumaric acid. Preferably tartaric acid is used.
Agentes armatizantes (1.5) incluem mas não são restritos a Tutti Frutti, morango, banana e baunilha. De preferência é utilizado Tutti Frutti.Artemisating agents (1.5) include but are not restricted to Tutti Frutti, strawberry, banana and vanilla. Tutti Frutti is preferably used.
Agentes edulcorantes (1.6) apropriados de acordo com a invenção incluem mas não são restritos a: Aspartame, acessulfame de potássio, sacarina, sacarina sódica, ciclamato de sódio, sucralose. Preferivelmente os agentes edulcorantes usados são aspartame e acessulfame de potássio.Suitable sweetening agents (1.6) according to the invention include but are not restricted to: Aspartame, acesulfame potassium, saccharin, sodium saccharin, sodium cyclamate, sucralose. Preferably the sweetening agents used are aspartame and acesulfame potassium.
Agentes aromatizantes adicionados, como anteriormente mencionado, e/ou agentes edulcorantes, como anteriormente mencionado, possuem a vantagem de aumentar a aceitação.Added flavoring agents as mentioned above and / or sweetening agents as mentioned above have the advantage of increasing the acceptance.
Como lubrificantes (1.7) um ou mais dos seguintes podem ser usados estearato de Mg, AI ou Ca, ácido esteárico, estearil-fumarato de sódio, talco, benzoato de sódio, mono-ácido graxo de glicerilo, p.ex. possuindo um peso molecular de 200 a 800 Daltons, p.ex. monoestearato de glicerilo (p.ex. Danisco, UK) , dibeenato de glicerilo (p.ex. CompritolAT0888™, Gattefossé France), gliceril-palmito-esteárico-éster (p.ex. Precirol™, Gattefossé France), poli (etileno-glicol) (PEG, BASF), óleo de semente de algodão hidrogenado (Lubitab, Edward Mendell Co Inc.), óleo de semente de rícino (Cutina HR, Henkel) e ésteres de sacarose (Surfhope SE, Mitsubishi-Kagaku Foods Co.). 6As lubricants (1.7) one or more of the following may be used Mg, Al or Ca stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl mono fatty acid, e.g. having a weight (eg Danisco, UK), glyceryl dibehenate (eg Compritol AT0888 ™, Gattefossé France), glyceryl-palmito-stearic ester (e.g., glyceryl monostearate ester (e.g. Precirol ™, Gattefossé France), poly (ethylene glycol) (PEG, BASF), hydrogenated cottonseed oil (Lubitab, Edward Mendell Co Inc.), castor oil (Cutina HR, Henkel) and sucrose (Surfhope SE, Mitsubishi-Kagaku Foods Co.). 6
Preferivelmente, é usado estearato de magnésio, sozinho ou em combinação com dibeenato de glicerilo.Preferably, magnesium stearate is used alone or in combination with glyceryl dibehenate.
Será reconhecido que qualquer excipiente dado pode servir com mais do que uma função p.ex. como carga, desintegrante, aglutinante, agente de deslizamento e/ou lubrificante.It will be recognized that any given excipient may serve with more than one function eg as filler, disintegrant, binder, slip agent and / or lubricant.
Verificou-se que a presença de um agente acidulante (1.4) diminui a solubilidade do composto I, evitando assim o gosto amargo de composto I quando o comprimido é dispersado em água p.ex. em uma colher antes da administração. 0 gosto amargo de composto I também pode ser suplantado pelo uso de agentes aromatizantes (1.5) e/ou de agentes edulcorantes (1.6). De acordo com a presente invenção, a quantidade de carga (1.1) pode variar dentro de uma faixa de 40% a 85%, em particular 63% a 78% em peso baseada no peso total de comprimido dispersivel. A quantidade de desintegrante (1.2) pode variar dentro de uma faixa de 0,5% a 20%, p.ex. 1% a 15% em peso baseada no peso total de comprimido dispersivel. A quantidade de agente de deslizamento (1.3) pode variar dentro da faixa de 0,1% a 5%%, em particular 0,1% a 2,5%, especialmente 0,5% a 1,0% em peso baseada no peso total de comprimido dispersivel. A quantidade de agente acidulante (1.4) pode variar dentro da faixa de 0,5% a 13%, em particular 1% a 8% em peso baseada no peso total de comprimido dispersivel. A quantidade de agente aromatizante (1.5) pode variar de 1% a 15%, preferivelmente de 2% a 10% em peso baseada no peso total de comprimido dispersivel. 7 A quantidade de agente edulcorante (1. 6) pode variar de 0,1% a 10%, preferivelmente de 0,2% a 8%. A quantidade de lubrificante (1.7) pode variar de 0,05% a 7%, preferivelmente de 0,1% a 3,0%. O comprimido dispersivel compreende os seguintes excipientes farmaceuticamente aceitáveis: uma ou mais cargas (1.1), especialmente numa quantidade total de 40% a 85%, preferivelmente de 63% a 78%, em peso baseada no peso total de comprimido dispersivel, um ou mais desintegrantes (1.2), especialmente numa quantidade total de 0,5% a 20%, preferivelmente de 1% a 15%, em peso baseada no peso total de comprimido dispersivel, um ou mais agentes de deslizamento (1.3), especialmente numa quantidade total de 0,1% a 5%%, preferivelmente de 0,5% a 1,0%, em peso baseada no peso total de comprimido dispersivel, um ou mais agentes acidulantes (1.4), especialmente numa quantidade total de 0,5% a 13%, preferivelmente de 1% a 8%, em peso baseada no peso total de comprimido dispersivel, um ou mais agentes aromatizantes (1.5), especialmente numa quantidade total de 1% a 15%, preferivelmente de 2% a 10%, em peso baseada no peso total de comprimido dispersivel, um ou mais agentes edulcorantes (1.6), especialmente numa quantidade total de 0,1% a 10%, preferivelmente de 0,2% a 8%, em peso baseada no peso total de comprimido dispersivel, e um ou mais lubrificantes (1.7), especialmente numa quantidade total de 0,05% a 7%, preferivelmente de 0,1% a 3,0%, em peso baseada no peso total de comprimido dispersivel.It has been found that the presence of an acidulating agent (1.4) decreases the solubility of the compound I, thus avoiding the bitter taste of compound I when the tablet is dispersed in water e.g. in a spoon prior to administration. The bitter taste of compound I can also be supplanted by the use of flavoring agents (1.5) and / or sweetening agents (1.6). According to the present invention, the amount of filler (1.1) can vary within a range from 40% to 85%, in particular 63% to 78% by weight based on the total weight of the dispersible tablet. The amount of disintegrant (1.2) may vary within a range of 0.5% to 20%, eg 1% to 15% by weight based on the total weight of the dispersible tablet. The amount of glidant (1.3) may vary within the range of 0.1% to 5%, in particular 0.1% to 2.5%, especially 0.5% to 1.0%, by weight based on total dispersible tablet weight. The amount of acidifying agent (1.4) may vary within the range of 0.5% to 13%, in particular 1% to 8% by weight based on the total weight of the dispersible tablet. The amount of flavoring agent (1.5) may range from 1% to 15%, preferably from 2% to 10% by weight based on the total weight of the dispersible tablet. The amount of sweetening agent (1.6) may range from 0.1% to 10%, preferably from 0.2% to 8%. The amount of lubricant (1.7) may range from 0.05% to 7%, preferably from 0.1% to 3.0%. The dispersible tablet comprises the following pharmaceutically acceptable excipients: one or more fillers (1.1), especially in a total amount of from 40% to 85%, preferably from 63% to 78%, by weight based on the total weight of the dispersible tablet, one or more (1.2), especially in a total amount of 0.5% to 20%, preferably 1% to 15%, by weight based on the total weight of the dispersible tablet, one or more slip agents (1.3), especially in a total amount preferably from 0.5% to 1.0% by weight based on the total weight of the dispersible tablet, one or more acidifying agents (1.4), especially in a total amount of 0.5% to 13%, preferably from 1% to 8%, by weight based on the total weight of the dispersible tablet, one or more flavoring agents (1.5), especially in a total amount of 1% to 15%, preferably 2% to 10%, by weight based on the total weight of the dispersible tablet, one or more sweetening agents (1.6), spec in a total amount of 0.1% to 10%, preferably 0.2% to 8%, by weight based on the total weight of the dispersible tablet, and one or more lubricants (1.7), especially in a total amount of 0.05 % to 7%, preferably 0.1% to 3.0%, by weight based on the total weight of the dispersible tablet.
As quantidades absolutas de cada excipiente farmaceuticamente aceitável e as quantidades relativas a outros excipientes farmaceuticamente aceitáveis são dependentes das propriedades desejadas do comprimido 8 dispersível e podem ser escolhidas por experimentação rotineira.The absolute amounts of each pharmaceutically acceptable excipient and the amounts relative to other pharmaceutically acceptable excipients are dependent on the desired properties of the dispersible tablet and may be chosen by routine experimentation.
Os comprimidos da invenção são dispersiveis, p.ex. em meios aquosos tal como água. Os comprimidos assim podem ser dispersados em p.ex. água antes da administração, que é uma forma conveniente de administração para crianças. Isto também acarreta uma aceitação melhor do paciente. Os comprimidos dispersiveis da presente invenção possuem um tempo de desintegração menor do que 5 minutos ou preferivelmente menor do que 4 minutos. Em uma outra modalidade os comprimidos dispersiveis da presente invenção possuem um tempo de desintegração menor do que 3 minutos, preferivelmente menor do que 2 minutos ou mais preferido menor do que 1 minuto baseado no método de acordo com a European Pharmacopoeia.The tablets of the invention are dispersible, eg in aqueous media such as water. The tablets can thus be dispersed in eg water prior to administration, which is a convenient form of administration for children. This also entails a better acceptance of the patient. The dispersible tablets of the present invention have a disintegration time of less than 5 minutes or preferably less than 4 minutes. In another embodiment the dispersible tablets of the present invention have a disintegration time of less than 3 minutes, preferably less than 2 minutes or more preferred less than 1 minute based on the method according to the European Pharmacopoeia.
De acordo com a invenção, o processo para a preparação dos comprimidos dispersiveis compreende misturar os excipientes de fase II (cerca de 10-20 minutos) , adicionar a mistura na fase I e remisturar pelo mesmo periodo de tempo. Fase III é então adicionada na mistura de pó das fases I e II e misturada por cerca de 2-5 minutos e comprimida em comprimidos. Fase I compreende composto I e um ou mais excipientes farmaceuticamente aceitáveis que estão presentes em uma concentração maior do que 5% em peso baseada no peso total de comprimido dispersível.According to the invention, the process for the preparation of the dispersible tablets comprises mixing the phase II excipients (about 10-20 minutes), adding the mixture in step I and remixing for the same period of time. Phase III is then added into the powder mixture of phases I and II and blended for about 2-5 minutes and compressed into tablets. Step I comprises compound I and one or more pharmaceutically acceptable excipients which are present in a concentration greater than 5% by weight based on the total weight of the dispersible tablet.
Fase II compreende os excipientes farmaceuticamente aceitáveis que estão presentes em uma concentração menor do que 5% em peso baseada no peso total de comprimido dispersível com a excepção dos lubrificantes do tipo 9 estearato. Fase III compreende lubrificantes do tipo estearato.Step II comprises the pharmaceutically acceptable excipients which are present in a concentration of less than 5% by weight based on the total weight of the dispersible tablet with the exception of the stearate type lubricants. Stage III comprises stearate type lubricants.
Procedimentos que podem ser usados podem ser convencionais ou conhecidos na arte ou baseados em tais procedimentos p.ex. aqueles descritos em L. Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd Ed., 1986; H. Sucker et al., Pharmazeutische Technologie, Thieme, 1991; Hagers Handbuch der pharmazeutischen Praxis, 4th Ed. (Springer Verlag, 1971) e Remington's Pharmaceutical Sciences, 13th Ed., (Mack. Publ., Co., 1970) ou edições posteriores.Procedures which may be used may be conventional or known in the art or based on such procedures eg those described in L. Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd Ed., 1986; H. Sucker et al., Pharmazeutische Technologie, Thieme, 1991; Hagers Handbuch der pharmazeutischen Praxis, 4th Ed. (Springer Verlag, 1971) and Remington's Pharmaceutical Sciences, 13th Ed., (Mack. Publ., Co., 1970) or later editions.
Visto que o composto I é praticamente insolúvel em água, foi uma surpresa que não obstante o conhecimento de que compressão directa (i.e. compressão sem granulação húmida prévia) não intensifica a dissolução dos compostos com solubilidade baixa, o composto I exibe dissolução boa dos comprimidos dispersiveis da presente invenção obtidos pelos métodos de compressão directa.Since compound I is practically insoluble in water, it was surprising that notwithstanding the knowledge that direct compression (ie compression without prior wet granulation) does not enhance the dissolution of the compounds having low solubility, compound I exhibits good dissolution of the dispersible tablets of the present invention obtained by direct compression methods.
De facto, a dissolução de composto I de comprimidos dispersiveis da invenção é tal que mais do que 60%, especialmente mais do que 70% p/p de composto I é dissolvido dentro de 15 minutos quando testado em 900 mL de tampão fosfato (pH=6,8) com lauril-sulfato de sódio 0,1% p/v aquecido a 37°C e agitado a 100 rpm com uma pá como descrito na Farmacopeia norte-americana.In fact, the dissolution of the dispersible tablets compound I of the invention is such that more than 60%, especially more than 70% w / w of compound I is dissolved within 15 minutes when tested in 900 ml of phosphate buffer (pH = 6.8) with 0.1% w / v sodium lauryl sulfate heated to 37øC and stirred at 100 rpm with a paddle as described in the U.S. Pharmacopoeia.
Em um aspecto da invenção um ou mais lubrificantes podem ser pulverizados sobre o material em contacto com superfícies de ferramentas de prensagem, p.ex. perfuradores e/ou moldes, da máquina de comprimidos antes da compressão. 10 A estabilidade fisica e quimica dos comprimidos dispersiveis pode ser testada em maneira convencional, p.ex. por medição de dissolução, friabilidade, tempo de desintegração, ensaio para produtos de desintegração de composto I, aparência e/ou microscopia, p.ex. após armazenagem na temperatura ambiente, i.e. 25°C/60% H.R. (humidade relativa), e/ou armazenagem a 40°C/75% H.R.. A velocidade de dissolução é estável no decorrer do tempo e em condições de armazenagem diferentes. Em uma modalidade preferida, a velocidade de dissolução dos comprimidos é estável durante pelo menos 6 meses quando são armazenados a 25°C/60% H.R. e 40°C/75% H.R. Os comprimidos dispersiveis podem variar em forma e serem, por exemplo, redondos, ovais, oblongos, cilíndricos, forma de trevo ou qualquer outra forma adequada.In one aspect of the invention one or more lubricants may be sprayed onto the material in contact with surfaces of pressing tools, eg punches and / or molds, of the tablet machine prior to compression. The physical and chemical stability of the dispersible tablets can be tested in conventional manner, e.g. by dissolution measurement, friability, disintegration time, test for compound I disintegration products, appearance and / or microscopy, e.g. after storage at room temperature, ie 25øC / 60% RH (relative humidity), and / or storage at 40øC / 75% RH The dissolution rate is stable over time and under different storage conditions. In a preferred embodiment, the dissolution rate of the tablets is stable for at least 6 months when stored at 25øC / 60% RH and 40øC / 75% RH. The dispersible tablets may be varied in shape and are, for example, round, oval, oblong, cylindrical, clover-shaped or any other suitable shape.
Em uma modalidade preferida da invenção comprimidos dispersiveis obtidos pelo método de compressão descrito acima são redondos ou estão na forma de trevo. As bordas dos comprimidos dispersiveis podem estar chanfradas ou arredondadas. Mais preferivelmente, os comprimidos dispersiveis estão na forma de trevo com bordas chanfradas. Os comprimidos dispersiveis de acordo com a invenção podem estar sulcados no centro ou estampados. 0 comprimido dispersivel de acordo com a invenção é preferivelmente de forma de trevo, dividido em quatro partes e de bordas chanfradas. O comprimido dispersivel possui um diâmetro variando entre 8 mm e 15 mm, mais preferivelmente entre 9 mm e 11 mm. Sua espessura varia de 2,5 mm a 4,5 mm, preferivelmente entre 2,9 mm e 3,9 mm. 11In a preferred embodiment of the invention dispersible tablets obtained by the compression method described above are round or in the form of clover. The edges of the dispersible tablets may be bevelled or rounded. More preferably, the dispersible tablets are in the form of clover with bevelled edges. The dispersible tablets according to the invention may be center-scored or embossed. The dispersible tablet according to the invention is preferably clover-shaped, divided into four parts and bevelled edges. The dispersible tablet has a diameter ranging from 8 mm to 15 mm, more preferably from 9 mm to 11 mm. Its thickness ranges from 2.5 mm to 4.5 mm, preferably between 2.9 mm and 3.9 mm. 11
Os comprimidos dispersiveis da invenção compreendendo cerca de 32 mg de composto I como grupo activo podem possuir uma dureza de cerca de 50 N a 120 N, preferivelmente 60 N a 100 N.The dispersible tablets of the invention comprising about 32 mg of compound I as the active group may have a hardness of about 50 N to 120 N, preferably 60 N to 100 N.
Os comprimidos dispersiveis da invenção podem estar coloridos e/ou ser comercializados de modo a proporcionar uma aparência individual e de torná-los instantaneamente reconhecíveis. O uso de corantes também pode servir para intensificar a aparência para identificar os comprimidos dispersiveis. Corantes adequados para uso em farmácia tipicamente incluem carotenóides, óxidos de ferro ou clorofila. Os comprimidos dispersiveis da invenção podem ser comercializados usando um código de impressão.The dispersible tablets of the invention may be colored and / or marketed so as to provide an individual appearance and make them instantly recognizable. The use of colorants may also serve to intensify the appearance to identify the dispersible tablets. Suitable dyes for use in pharmacy typically include carotenoids, iron oxides or chlorophyll. The dispersible tablets of the invention may be marketed using a printing code.
Os comprimidos dispersiveis da presente invenção são úteis para o tratamento de PAH e exibem um perfil farmacocinético bom. Os comprimidos dispersiveis da presente invenção podem ser administrados p.ex. duas vezes ao dia com uma dosagem efectiva de ingrediente activo composto I dentro da faixa de 2 mg/kg a 4 mg/kg de peso corporal. O comprimido pode ser acondicionado em qualquer blister possível conhecido na arte, como por exemplo em blisters de alumínio. Como pode ser visto da figura 1, a formulação pediátrica tem demonstrado absorção baseada em dados de pk. Os seguintes exemplos não limitantes ilustram a invenção. 12The dispersible tablets of the present invention are useful for the treatment of PAH and exhibit a good pharmacokinetic profile. The dispersible tablets of the present invention may be administered e.g. twice daily with an effective dosage of active ingredient compound I within the range of 2 mg / kg to 4 mg / kg body weight. The tablet may be packaged in any possible blister known in the art, for example in aluminum blisters. As can be seen from figure 1, the pediatric formulation has demonstrated absorption based on pk data. The following non-limiting examples illustrate the invention. 12
Exemplo 1Example 1
Componentes Quantida de poi comprimido [mg] Percentual [p/p] Fase I Composto I como mono-hidrato, micronizado 33,045 11,39 Celulose microcristalina (1.1) 116,265 05 O o 'vt1 Fosfato de dicálcio (1.1) 101,500 35, 00 Fase II Croscarmelose de sódio (1.2) 11,600 O o Dióxido de silício coloidal (1.3) 2,900 1,00 Ácido tartárico (1.4) 7,000 2,41 Tutti Frutti (1.5) 9,000 O 1—1 PO Aspartame (1.6) 3,700 1,28 Acessulfame de potássio (1.6) 1,800 0, 62 13Ingredients Amount of tablet [mg] Percent [w / w] Phase I Compound I as micronized monohydrate 33.045 11.39 Microcrystalline cellulose (1.1) 116.265 05 Ovt1 Dicalcium phosphate (1.1) 101,500 35.00 Phase (1.3) 2,900 1.00 Tartaric acid (1.4) 7,000 2.41 Tutti Frutti (1.5) 9,000 O 1-1 PO Aspartame (1.6) 3,700 1.28 Acesulfame (1.2) 11.600 O Colloidal silicon dioxide of potassium (1.6) 1,800 0.62
Fase III Estearato de magnésio (1.7) 3,190 1,1 Total 290Phase III Magnesium stearate (1.7) 3.190 1.1 Total 290
Propriedades do comprimido:Tablet Properties:
Parâmetros Valor Diâmetro 10 mm Friabilidade < 0,3 % Desintegração a 15-22°C (EP) < 40 s Dissolução, média de 6 comprimidos Método da pá, 100 rpm, tampão fosfato a pH = 6,8 com lauril-sulfato de sódio 0,1%, 37°C Mais do que 75° em 15 minutosParameters Value Diameter 10 mm Friability < 0.3% Disintegration at 15-22 ° C (EP) < 40 s Dissolution, average of 6 tablets Paddle method, 100 rpm, phosphate buffer at pH = 6.8 with 0.1% sodium lauryl sulfate, 37øC More than 75ø in 15 minutes
Exemplo 2Example 2
Componentes Quantidade por comprimido [mg] Percentual [p/p] Fase I Composto I como mono-hidrato 33,045 11,80 Celulose microcristalina (1.1) 135,200 48,29 Fosfato de dicálcio (1.1) 70,000 25,00 14Components Amount per tablet [mg] Percent [w / w] Phase I Compound I as monohydrate 33.045 11.80 Microcrystalline cellulose (1.1) 135,200 48.29 Dicalcium phosphate (1.1) 70,000 25.00 14
Componentes Quantidade por comprimido [mg] Percentual [p/p] Fase II Croscarmelose de sódio (1.2) 11,200 4,00 Dióxido de silício coloidal (1.3) 2,800 1,00 Ácido tartárico (1.4) 6,250 2,23 Tutti Frutti (1.5) 9,000 3,21 Aspartame (1.6) 3,700 1,32 Acessulfame de potássio (1.6) 1,800 0,64 Dibeenato de glicerila (1.7) 5, 600 2,00 Fase III Estearato de magnésio (1.7) 1,400 0,50 Total 280 15Ingredients Amount per tablet [mg] Percent [w / w] Phase II Croscarmellose sodium (1.2) 11,200 4.00 Colloidal silicon dioxide (1.3) 2,800 1.00 Tartaric acid (1.4) 6.250 2.23 Tutti Frutti (1.5) 9,000 3.21 Aspartame (1.6) 3,700 1.32 Acesulfame potassium (1.6) 1,800 0.64 Glyceryl dibehenate (1.7) 5.6 Phase III Magnesium stearate (1.7) 1.400 0.50 Total 280 15
Propriedades do comprimido: parâmetros Valor Diâmetro 10 mm Friabilidade < 0,3 %0 Desintegração a 15-22°C (EP) < 40 s Dissolução, média de 6 comprimidos Método da pá, 100 rpm, tampão fosfato a pH = 6,8 com lauril-sulfato de sódio 0,1%, 37°C Mais do que 75% em 15 minutosTablet Properties: parameters Value Diameter 10 mm Friability < 0.3% Disintegration at 15-22 ° C (EP) < 40 s Dissolution, average of 6 tablets Paddle method, 100 rpm, phosphate buffer at pH = 6.8 with 0.1% sodium lauryl sulfate, 37øC More than 75% in 15 minutes
Exemplo 3Example 3
Componentes Quantidade por comprimido [mg] Percentual [p/p] Fase I Composto I como mono-hidrato 33,045 15,74 Celulose microcristalina (1.1) 79,765 37,98 Fosfato de dicálcio (1.1) 63,000 30,00 Fase II Croscarmelose de sódio (1.2) 8,400 4,00 Dióxido de silicio coloidal 2,100 1,00 16 (1.3) Ácido tartárico (1.4) 6,250 2,98 Morango (1.5) 9,000 4,29 Aspartame (1.6) 3,700 1,76 Acessulfame de potássio (1.6) 1,800 0,86 Fase III Estearato de magnésio (1.7) 2,940 O T—1 Total 210Ingredients Amount per tablet [mg] Percent [w / w] Phase I Compound I as monohydrate 33.045 15.74 Microcrystalline cellulose (1.1) 79.765 37.98 Dicalcium phosphate (1.1) 63,000 30.00 Phase II Croscarmellose sodium 1.2) 8.400 4.00 Colloidal silicon dioxide 2.100 1.00 16 (1.3) Tartaric acid (1.4) 6.250 2.98 Strawberry (1.5) 9,000 4.29 Aspartame (1.6) 3.700 1.76 Potassium acesulfame (1.6) 1,800 0.86 Phase III Magnesium stearate (1.7) 2,940 OT-1 Total 210
Propriedades do comprimido: parâmetros Valor Diâmetro 9 mm Friabilidade < 0,3 % Desintegração a 15-22°C (EP) < 40 s Dissolução, média de 6 comprimidos Método da pá, 100 rpm, tampão fosfato a pH = 6,8 com lauril-sulfato de sódio 0,1%, 37°C Mais do que 75% em 15 minutos 17Tablet Properties: parameters Value Diameter 9 mm Friability < 0.3% Disintegration at 15-22 ° C (EP) < 40 s Dissolution, average of 6 tablets Spray method, 100 rpm, phosphate buffer at pH = 6.8 with 0.1% sodium lauryl sulfate, 37øC More than 75% in 15 minutes 17
REFERÊNCIAS CITADAS NA DESCRIÇÃOREFERENCES CITED IN DESCRIPTION
Esta lista das referências citadas pelo requerente serve apenas para conveniência do leitor. Não é parte integrante do documento da patente europeia. Apesar da compilação cuidadosa das referências, os erros ou as omissões não podem ser excluídos e o IEP rejeita toda a responsabilidade a este respeito.This list of references cited by the applicant is for the reader's convenience only. It is not an integral part of the European patent document. Despite the careful compilation of references, errors or omissions can not be excluded and the IEP rejects all responsibility in this regard.
Documentos de patente citados na descrição:Patent documents cited in the disclosure:
• EP 0526708 AI• EP 0526708 AI
Literatura, não relacionada com patentes, citada na descrição: • Handbook of Pharmaceutical Excipients. American Pharmaceutical Association, Washington, USA and Pharmaceutical Press [0012] • Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete. Edito Cantor [0012] • L. Lachman et al. The Theory and Practice of Industrial Pharmacy. 1986 [0039] • H. Sucker et al. Pharmazeutische Technologie. Thieme, 1991 [0039] • Hagers Handbuch der pharmazeutischen Praxis Springer Verlag, 1971 [0039] • REMINGTON'S PHARMACEUTICAL SCIENCES. MACK PUBL., CO, 1970 [0039]Literature, not related to patents, cited in the description: • Handbook of Pharmaceutical Excipients. American Pharmaceutical Association, Washington, USA and Pharmaceutical Press [0012] • Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete. Edito Cantor [0012] • L. Lachman et al. The Theory and Practice of Industrial Pharmacy. 1986 [H. Sucker et al. Pharmazeutische Technologie. Thieme, 1991 • Hagers Handbuch der pharmazeutischen Praxis Springer Verlag, 1971 • REMINGTON'S PHARMACEUTICAL SCIENCES. MACK PUBL., CO, 1970 [0039]
Lisboa, 16/02/2010Lisbon, 02/16/2010
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| NZ564167A (en) | 2005-05-17 | 2009-12-24 | Actelion Pharmaceuticals Ltd | Dispersible tablet comprising 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulfonamide (bosutan) |
| US8664390B2 (en) | 2007-06-29 | 2014-03-04 | Generics (Uk) Limited | Process for the introduction of hydroxyethoxy side chain in bosentan |
| CA2712860C (en) | 2008-02-08 | 2014-11-18 | Abhay Gaitonde | Process for preparing bosentan |
| JP2012507497A (en) | 2008-11-03 | 2012-03-29 | ジェネリクス・（ユーケー）・リミテッド | HPLC analysis methods for bosentan and related substances, and use of these substances as reference standards or markers |
| JP5850576B2 (en) * | 2010-07-06 | 2016-02-03 | 富士化学工業株式会社 | Bosentan solid dispersion |
| CN102114005B (en) * | 2010-12-06 | 2012-12-12 | 武汉武药科技有限公司 | Tracleer capsule and preparation method thereof |
| EP2696857A1 (en) | 2011-04-11 | 2014-02-19 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Pharmaceutical composition comprising bosentan |
| WO2012166899A2 (en) | 2011-06-03 | 2012-12-06 | Eisai R&D Management Co., Ltd. | Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds |
| CN104487057A (en) | 2012-05-11 | 2015-04-01 | 韩诺生物制药株式会社 | Bosentan controlled release oral preparation |
| KR101451327B1 (en) * | 2013-01-08 | 2014-11-03 | 안국약품 주식회사 | Controlled release multi-compressed tablet of bosetan and its preparing method |
| RU2559424C1 (en) * | 2014-06-18 | 2015-08-10 | Федеральное государственное бюджетное учреждение "Российский кардиологический научно-производственный комплекс" Министерства здравоохранения Российской Федерации (ФГБУ "РКНПК" Минздрава России) | Method for selecting drug therapy for patients with idiopathic pulmonary arterial hypertension |
| RS63559B1 (en) | 2014-08-28 | 2022-10-31 | Eisai R&D Man Co Ltd | High-purity quinoline derivative and method for manufacturing same |
| PL3263106T3 (en) | 2015-02-25 | 2024-04-02 | Eisai R&D Management Co., Ltd. | Method for suppressing bitterness of quinoline derivative |
| CN104840965B (en) * | 2015-05-05 | 2018-05-08 | 重庆华邦制药有限公司 | The preparation and its stabilizer of Bosentan |
| KR20160141045A (en) | 2015-05-27 | 2016-12-08 | 한올바이오파마주식회사 | Pharmaceutical composition containing of Bosentan |
| BR112017027227B1 (en) | 2015-06-16 | 2023-12-12 | Eisai R&D Management Co., Ltd | ANTI-CANCER AGENT |
| CN108703956A (en) * | 2018-08-21 | 2018-10-26 | 天津双硕医药科技有限公司 | A kind of solid composite medicament containing Bosentan |
| CA3161960A1 (en) | 2019-12-16 | 2021-06-24 | Tenax Therapeutics, Inc. | Levosimendan for treating pulmonary hypertension with heart failure with preserved ejection fraction (ph-hfpef) |
| WO2023107066A2 (en) * | 2021-12-07 | 2023-06-15 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Bosentan pharmaceutical compositions |
| WO2023128902A1 (en) * | 2021-12-30 | 2023-07-06 | Pharmactive Ilac Sanayi Ve Ticaret A.S. | Pharmaceutical compositions comprising bosentan and relevant excipients |
| CN114533738A (en) * | 2022-02-19 | 2022-05-27 | 苏州海景医药科技有限公司 | Bosentan solid pharmaceutical composition and preparation method thereof |
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| RU2086544C1 (en) * | 1991-06-13 | 1997-08-10 | Хоффманн-Ля Рош АГ | Benzenesulfonamide derivatives of pyrimidine or their salts, pharmaceutical composition for treatment of diseases associated with endothelin activity |
| ES2082723B1 (en) * | 1994-07-20 | 1996-10-01 | Lilly Sa | PHARMACEUTICAL FORMULATION OF FLUOXETINE IN A DISPERSIBLE FORM. |
| US6635648B2 (en) * | 2000-08-18 | 2003-10-21 | Queen's University At Kingston | Combination therapy using sympathetic nervous system antagonists and endothelin antagonists |
| AR040233A1 (en) * | 2002-05-31 | 2005-03-23 | Schering Corp | XANTINA FOSFODIESTERASA V INHIBITING POLYMORPHES |
| KR100604034B1 (en) | 2003-10-08 | 2006-07-24 | 주식회사유한양행 | A composition of fast dissolving tablets containing amlodipine free base |
| NZ564167A (en) | 2005-05-17 | 2009-12-24 | Actelion Pharmaceuticals Ltd | Dispersible tablet comprising 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulfonamide (bosutan) |
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